Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

• Published in: Cancer science Vol. 111; no. 8; pp. 2682 - 2688
• Main Authors: Edahiro, Yoko, Araki, Marito, Komatsu, Norio
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2020; John Wiley and Sons Inc
• Subjects: Amino acids; Animals; Asparagine; Bone marrow; Calreticulin; Calreticulin - genetics; Calreticulin - metabolism; Cell surface; Cell Transformation, Neoplastic - genetics; chaperone protein; Cytokines; Disease Models, Animal; Endoplasmic reticulum; Endoplasmic Reticulum - immunology; Endoplasmic Reticulum - pathology; Frameshift Mutation; Gene Expression Regulation, Neoplastic; Genetic transformation; Glycoproteins; Hematologic Neoplasms - genetics; Hematologic Neoplasms - immunology; Hematologic Neoplasms - pathology; Hematopoietic Stem Cells - pathology; Homeostasis; Humans; Immune response; Immunomodulation; JAK2 V617F; Janus kinase 2; Janus Kinase 2 - metabolism; Kinases; Leukemia; Molecular modelling; Mutants; Mutation; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - immunology; Myeloproliferative Disorders - pathology; myeloproliferative neoplasm; Proteins; Proto-Oncogenes - genetics; Receptor mechanisms; Receptors, Thrombopoietin - metabolism; Review; Signal Transduction - genetics; Signal Transduction - immunology; Thrombopoietin; thrombopoietin receptor; Transcription; Transcription, Genetic; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors; thrombopoietin receptor; calreticulin; JAK2 V617F; myeloproliferative neoplasm; chaperone protein
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14503

Deregulation of cytokine signaling is frequently associated with various pathological conditions, including malignancies. In patients with myeloproliferative neoplasms (MPNs), recurrent somatic mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone that resides in the endoplasmic reticulum, have been reported. Studies have defined mutant CALR as an oncogene promoting the development of MPN, and deciphered a novel molecular mechanism by which mutant CALR constitutively activates thrombopoietin receptor MPL and its downstream molecules to induce cellular transformation. The mechanism of interaction and activation of MPL by mutant CALR is unique, not only due to the latter forming a homomultimeric complex through a novel mutant‐specific sequence generated by frameshift mutation, but also for its ability to interact with immature asparagine‐linked glycan for eventual engagement with immature MPL in the endoplasmic reticulum. The complex formed between mutant CALR and MPL is then transported to the cell surface, where it induces constitutive activation of downstream kinase JAK2 bound to MPL. Refined structural and cell biological studies can provide an in‐depth understanding of this unusual mechanism of receptor activation by a mutant molecular chaperone. Mutant CALR is also involved in modulation of the immune response, transcription, and intracellular homeostasis, which could contribute to the development of MPN. In the present article, we comprehensively review the current understanding of the underlying molecular mechanisms for mutant molecular chaperone‐induced cellular transformation. In the present review, we would like to propose a novel and exciting model: mutant molecular chaperone serves as a ligand to constitutively activate a cytokine receptor on the cell surface for the induction of cellular transformation.